Many pathogens enter and reside in barrier tissues of the skin and lung. Pathogen control ultimately requires the recruitment and activation of immune effectors to specific infected tissue micro-environments. While we have gained much insight into effector T cell generation in lymphoid tissues there exists a significant knowledge gap on the fate of effector T cells once they leave the lymph node. Yet it is within the inflamed tissue milieu that T cells must mediate their effector functions, including cytokine secretion and cytolysis, to clear the infection. The central hypothesis is that the specific tissue and the local inflammatory milieu will shape T cell recruitment and effector function. Such tissue-control is likely to impact the magnitude and functional diversity of the immune response. Optimizing T cell function in tissues is critical for pathogen clearance and the avoidance of collateral damage. The goal of this proposal is to define the checkpoints and identify molecular interactions that guide successful immunity at sites of inflammation. The objective of this Program Project is to bring together scientific expertise in migration and effector function to address fundamental effector T cell processes in infected tissues using cutting-edge intra-vital imaging approaches. When effector T cells enter the inflamed tissue they encounter a tissue environment that has been differentially altered depending on the type of pathogen and corresponding inflammation. The ability of T cells sense and interpret different inflammatory environments and the impact on effective pathogen clearance are poorly understood. Project 1 (Dr. Minsoo Kim) addresses how neutrophils modify the micro-environment and how T cells integrate multiple tissue-specific inflammatory cues. Project 2 (Dr. Deborah Fowell) determines how the altered milieu controls the mechanisms used by effector T cells to migrate and survey the tissue for antigen-bearing APC/infected cells. Project 3 (Dr. David Topham) focuses on how the inflamed lung tissue modifies CDS migration and impacts on the development of long-term tissue memory to influenza infection. These processes are critical to the clearance of pathogens but also support the activation of immunity in chronic inflammation, autoimmune and allergic settings. Using innovative tools for in situ modulation and visualization of immune responses in the skin and lung we will define the molecular parameters for effector T cell movement and function at distinct sites of inflammation.
Inflammation is critical for pathogen clearance but is also pathogenic in many settings from autoimmunity to cardiovascular disease. Identifying the molecular parameters for effector T cell migration and function within tissues should enable the design of targeted therapeutics for inflammation-specific or location-specific manipulation of T cells to ameliorate damaging inflammation or promote beneficial inflammation.
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